Interest in angiogenesis is evidenced by the vast amount of literature available on the subject, some of which is over one hundred years old. See, e.g., Virchau, R., Die Krankhaftern Geshwulste, Hirshwald, Berlin (1863); Thierisch, C., Die Hautmit Altas, Leipzig (1865). "Angiogenesis" is defined as the process by which new blood vessels are formed, with accompanying increased blood circulation. Much of the research in this field over the past ten years has concentrated on identifying and purifying naturally occurring substances which cause angiogenesis Examples of the literature in this area include Weiss, et al., Br. J. Cancer 40: 493-96 (1979); Fencelau, et al., J. Biol. Chem. 256: 9605-9611 (1981); McAslan, et al., Exp. Cell Res. 119: 181-190 (1979), which show that angiogenic factors are present in tissues of pathological origin, such as tumor cells. Kumar, et al., Lancet 2: 364-367 (1983); and Brown, et al., Lancet 1: 682-685 (1980), show an angiogenesis factor in synovial fluid of arthritis patients, while Hill, et al., Experentia 39: 583-585 (1983) show one in vitreum, of arthritic patients. Banda, et al., Proc. Natl. Acad. Sci. 79: 7773-7777 (1982), teach one in wound fluid. Additional teachings in this field include those of D'Amore, et al., Proc. Natl. Acad. Sci. 78: 3068-3072 (1981); Kissun, et al., Br. J. Ophthalmol. 66: 165-159 (1982); DeCarvellho, et al., Angiology 34: 231-243 (1983); Frederick, et al., Science 224: 289-290 (1980); Burgos, Eur. J. Clin. Invest 13: 289-296 (1983); and Catellot, et al., Proc. Natl Acad. Sci. 79: 5597-5601 (1982), all of which show the existence of angiogenic factors in normal tissues.
Characteristic of all of the angiogenic materials discussed in the above referenced prior art is that they are involved in normal growth and development. In other words, angiogenesis is a necessary process during the growth and development of an individual organism. The prior art angiogenic factors described supra are involved in these normal processes, but are apparently not implicated in enhanced rates of angiogenesis, which is sometimes necessary or desirable.
The first research into factors provoking enhanced angiogenesis is to be found in Goldsmith, et al., JAMA 252: 2034-2036 (1984). The factor was found in chloroform-methanol fractionates of feline omentum. This research is presented in U.S. Pat. No. 4,699,788, the disclosure of which is incorporated herein. This extract is a lipid extract.
Additional research based upon the teachings of Goldsmith, et al. found that the class of glycolipids known as gangliosides possesses enhanced angiogenic activity. This may be seen in U.S. Pat. No. 4,710,490, the disclosure of which is incorporated by reference herein.
It will be seen that the newest research on angiogenesis points to lipid containing molecules as provoking enhanced angiogenesis. This was new to the art, as the earlier literature all suggested that protein derived material caused angiogenesis. Thus, Kumar, et al., Lancet 2: 364-367 (1983) teach proteins of from 300 to 105 daltons, while Kissun, et al., Br. J. Ophthalmol 66: 165-169 (1982), show protein factors weighing up to 70 kilodaltons. Banda, et al., Proc. Natl. Acad. Sci. 79: 7773-7777 (1982), teach proteins of from 2 to 14 kilodaltons as provoking angiogenesis and Burgos, et al., Eur. J. Clin. Invest 13: 289-296 (1983), show protein complexes of from 100 to 200 kilodaltons. A very recent report, by van Brunt, et al., Biotechnology 6(1): 25-30 (Jan. 1988) describes angiogenesis caused by proteins.
The art, however, contains no mention of angiogenesis, either normal or enhanced, caused by oligosaccharides "Oligosaccharides" as defined, e.g., by Steadman's Medical Dictionary (Williams & Wilkins, 1982), Baltimore, at 980, are compounds "made up of the condensation of a small number of monosaccharide units". For purposes of this application, the "small number" referred to by Steadman's is defined to be 2 or greater, as well as monosaccharides which contain at least one substituted group. Monosaccharides, of course, are the building blocks of oligosaccharides, sugars, carbohydrates, and starches, and are components of other materials, such as glycoproteins, glycolipids, and other larger, more complex molecules. Various monosaccharides are well known to the art including, but not being limited to glucose, galactose, mannose, etc. The art also knows that these monosaccharides interact with each other to form various polysaccharide or oligosaccharide materials. When these interact, they form bonds therebetween, which are represented by the carbon number of the participating monosaccharide and the conformation resulting from the bond (alpha or beta). Thus, the nomenclature 1.fwdarw.4 will mean that bonding took place between the first carbon of one monosaccharide and the fourth carbon of another, and the bond is in alpha configuration. The skilled artisan will be familiar with the terminology and nomenclature of oligosaccharide chemistry, and will recognize that the foregoing is merely one example of a myriad of possible oligosaccharide configurations, both simple and complex.
It has now been found that many oligosaccharides cause angiogenesis. The ability to cause this phenomenon does not appear to be linked to any bond configuration, number of monosaccharide units, or constituents of the molecule. In order to determine which oligosaccharides are and are not angiogenic, a simple mechanism is available. Such a method is described herein.
Hence it is an object of the invention to provide a method for causing angiogenesis in a subject in need of angiogenesis, comprising administering to said subject an angiogenically effective amount of an angiogenically active, pharmaceutically acceptable oligosaccharide. This administration may take a number of forms, and the oligosaccharide may be administered alone, or with other pharmaceutically acceptable substances, such as pharmaceutically acceptable carriers.
How this object, and other objects of the invention are accomplished will be seen from the disclosure which follows: